Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors

Eur J Med Chem. 2022 Jun 5:236:114311. doi: 10.1016/j.ejmech.2022.114311. Epub 2022 Mar 28.

Abstract

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 μM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.

Keywords: BRPF1; Bromodomain; Dual targeting inhibitor; Structure-guided design; TRIM24.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / antagonists & inhibitors
  • Animals
  • Carrier Proteins* / antagonists & inhibitors
  • Cell Line, Tumor
  • DNA-Binding Proteins* / antagonists & inhibitors
  • Humans
  • Male
  • Prostatic Neoplasms / drug therapy
  • Protein Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • BRPF1 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • TRIM24 protein, human